Tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, is useful for treating urinary incontinence. The major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamin e, contributes significantly to the therapeutic effect of tolterodine. Tolterodine and analogues thereof, including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in U.S. Pat. No. 5,382,600. The active metabolite and analogues are disclosed in U.S. Pat. No. 5,559,269. The (S)-enantiomer and its use in the treatment of urinary and gastrointestinal disorders is further described in WO 98/03067.
One of the processes described in U.S. Pat. No. 5,382,600 comprises the steps of preparing the lactone 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductively ring-opening the lactone to prepare the corresponding alcohol, reacting the alcohol with isopropylamine, and resolving the racemate formed to isolate tolterodine.
U.S. Pat. No. 5,922,914 discloses a modified process for preparing tolterodine by reducing the above-mentioned lactone to the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine.
While the above prior art methods thus produce a racemate which has to be resolved to obtain the desired tolterodine enantiomer, Andersson, Pher G. et al., J. Org. Chem. 1998, 63, 8067-8070 discloses an enantioselective synthesis of tolterodine which obviates the need of the enantiomer separation step. This method comprises a copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesium bromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the (5S)-phenyl-(3R)-(2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolid inone, hydrolyzation of the oxazolidinone to the corresponding propanoic acid, reaction with diisopropylamine to form the amide, and reduction of the amide to tolterodine.